Asthma is a major public health problem in the United States. Nearly 17 million Americans suffer from this often debilitating disease. Moreover, asthma morbidity and mortality have been rising over the last two decades. The prevalence rate of asthma increased by 75% from 1980 to 1994. And, despite the increased use of medications, the rate of asthma-related deaths rose 58% and now exceeds 180,000 annually. While the reasons for increased asthma morbidity and mortality remain unknown, it is hoped that improved approaches to asthma therapy will reverse this trend. See Redd S C. Asthma in the United States: burden and current theories. Environ Health Perspect 2002; 110 Suppl 4:557-560; and Kay A B. Asthma and inflammation. J. Allergy Clin. Immunol. 1991; 87:893-910.
Allergic asthma is characterized by airway hyper-responsiveness (AHR), airway inflammation, and elevated IgE. See Kay A B., Asthma and inflammation. J. Allergy Clin. Immunol. 1991; 87:893-910. This results in symptomatic effects including, but not limited to, episodic breathlessness, wheezing, chest tightness, and coughing. See Lemanske R F J, A review of the current guidelines for allergic rhinitis and asthma. J. Allergy Clin. Immunol. 1998; 101:S392-S396. Furthermore, the airways of asthmatic subjects are characterized by chronic inflammation with infiltration of the bronchial mucosa by lymphocytes, eosinophils and mast cells as well as epithelial desquamation, goblet cell hyperplasia, and thickening of the submucosa (airway remodeling). See Kay A B., Asthma and inflammation. J.Allergy Clin.Immunol. 1991; 87:893-910; McFadden E R J, Gilbert Iowa., Asthma. N Engl J Med 1992; 327:1928-1937; Beasley R, Roche W R, Roberts J A, Holgate S T, Cellular events in the bronchi in mild asthma and after bronchial provocation. Am.Rev.Respir.Dis. 1989; 139:806-817.
Human atopic subjects, when exposed to the relevant antigen (Ag), exhibit an acute IgE-dependent response, often followed by a late-phase inflammatory response (LPR) hours later. The immediate response is triggered by mast cell degranulation and release of mediators, such as histamine, tryptase, leukotrienes, and platelet-activating factor (PAF). LPR is associated with infiltration of inflammatory cells, predominantly eosinophils, which release eosinophil major basic protein, leukotrienes, and other mediators that damage the airway epithelium and induce bronchoconstriction. See Metzger W J, Huuiinghake G W, Richerson H B. Late asthmatic responses: inquiry into mechanisms and significance. Clin.Rev.Allergy 1985; 3:145-165; Busse W W, Vrtis R F, Dick E C. The role of viral infections in intrinsic asthma: activation of neutrophil inflammation. Agents Actions Suppl. 1989; 28:41-56; Lemanske R F, Kaliner M A. Late-phase allergic reactions. In: Middleton Jr, Reed C E, Ellis E F, Adkinson N F, Yunginger J W, eds. In Allergy: Principles and Practice. St. Louis: C. V. Mosby, Co., 1993: 320; Pauwels R. The relationship between airway inflammation and bronchial hyperresponsiveness. Clin.Exp.Allergy 1989; 19:395-398; Drazen J M, Arm J P, Austen K F. Sorting out the cytokines of asthma. J.Exp.Med. 1996; 183:1-5.
Numerous studies demonstrated that the Th2 cytokines, IL-4, IL-5 and IL-13 play a central role in the pathogenesis of asthma. For example, IL-4 and IL-13 induce B cell switching to IgE synthesis. This process favors Th2 cell differentiation, mast cell development, eosinophil and basophil activation, and airway remodeling including new collagen, goblet cell formation, and airway smooth muscle (ASM) hypertrophy. See Ware L B, Matthay M A. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002; 282:L924-L940. IL-4 and IL-13 can also increase ASM contraction perhaps by desensitizing β2 AR in ASM. IL-5 is responsible for eosinophil differentiation, maturation, and activation.
A major driving force behind chronic asthma is the long-lived memory Th2 cells that secrete Th2 cytokines following antigen encounter. These memory Th2 cells often arise early in life and persist following repeated encounters with allergen. Thus, targeting memory Th2 cells offers a therapeutic approach for asthma.
A Th2 transcription factor that is critical to Th2 cytokine memory is GATA-3, whose activation of Th2 cytokine gene expression is through chromatin remodeling. Therefore, immunomodulation of GATA-3 is important in down-regulating all critical Th2 cytokine production (IL-4, IL-5 and IL-13).
Because inflammation is a principal factor in AHR, attention has focused on reducing inflammatory processes. Corticosteroids, the most potent nonspecific anti-inflammatory agents, produce substantial improvement in objective lung functions of asthmatics and are still the cornerstone of asthma treatment. See Leonard P, Sur S. Asthma: future directions. Med Clin North Am 2002; 86:1131-1156. Corticosteroids, however, do not significantly improve airway remodeling, do not inhibit the release of mast cell mediators, have no direct bronchodilator activity, and at the same time, induce significant systemic adverse effects when given for prolonged periods. See Jain V V, Kitagaki K, Busing a T, Hussain I, George C, O'shaughnessy P, Kline J N. CpG-oligodeoxynucleotides inhibit airway remodeling in a muline model of chronic asthma. J Allergy Clin Immunol 2002; 110:867-872; and National Heart LaBI. Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute. National Asthma Education Program. Expert Panel Report. J Allergy Clin Immunol 1991; 88:425-534.
Although inhaled corticosteroids greatly reduce the side effects, systemic side effects of inhaled corticosteroids (ICS) also have been reported. Adrenal suppression, decreased bone metabolism, and decreased growth are a concern in children taking ICS. See WHO Study Group on Global Strategy for Asthma Management and Prevention. AnonymousGlobal strategy for asthma management and prevention. Bethesda, Md.: National Institutes of Health, 1995:95-3659; and Akinbami L J, Schoendorf K C. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 2002; 110:315-322. Corticosteroids also produce overall immune suppression, which results in increased susceptibility to infections. In addition, recent studies indicate that continuous daily treatment with ICS had no long-term therapeutic benefit in terms of lung function because although anti-inflammatory therapy reduced the incidence of asthma symptoms in subjects with persistent asthma, it did not alter progressive lung changes or prevent recurrence of symptoms shortly after discontinuation of therapy. The Childhood Asthma Management Program Research Group. Long-term effects of Budesonide or nedocromil in children with asthma. N Engl J Med 2000; 343:1054-1063. Additionally, two new classes of recently introduced asthma medications, leukotriene inhibitors and anti-IgE, have shown only marginal benefits.
In view of this, there remains an unmet need to develop alternative, safe, and effective asthma treatments. Although a role for complementary and alternative medicine (CAM) in asthma treatment is uncertain because of the lack of well controlled scientific studies, the use of CAM in Western countries has grown substantially over the last 10 years. See Steurer-Stey C, Russi E W, Steurer J. Complementary and alternative medicine in asthma: do they work? Swiss Med Wkly 2002; 132:338-344; MacLennan A H, Wilson D H, Taylor A W. Prevalence and cost of alternative medicine in Australia. Lancet 1996; 347:569-573; Kessler R C, Davis R B, Foster D F, Van Rompay M I, Walters E E, Wilkey S A, Kaptchuk T J, Eisenberg D M. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med 2001; 135:262-268; and Eisenberg D M, Kessler R C, Foster C, Norlock F E, Calkins D R, Delbanco T L. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med 1993; 328:246-252. One recent study found that up to 50% of asthmatics were using some form of CAM, and that a growing number of asthma patients wish to use some form of CAM.
Traditional Chinese Medicine (TCM), including the use of Chinese herbal medications (CHM), is one of the oldest medical practices in the world and has benefited patients for thousands of years. For example, the symptoms of asthma such as coughing, wheezing and chest tightness were described in the book Yellow Emperor's Inner Classic, which is thought to have been compiled in the first or second century C.E., by which time the theoretical foundations of TCM were in place. In addition to acupuncture, the most widely used TCM treatments are “herbal formulas” comprised of specific mixtures of several components. The combination of herbs is believed to produce synergistic effects and reduce possible side effects. Previous studies support this notion, indicating that some herbal formulas are more effective than their individual components. For example, the widely used anti-allergy formula TJ-19 (Traditional Chinese-Japanese herbal medicine) is known to more effectively inhibit histamine induced reactions than any of its individual herbal components. See Hosoya E, Yamamura Y. Recent advances in the pharmacology of kampo (Japanese herbal) medicines. Tokyo: Excerpta Medica, 1998:260.
Accordingly, the development of a TCM treatment for asthma comprising a manageable number of herbal ingredients is a desirable and unmet need. Additionally, the development of a TCM targeting Th2 transcription factor is also a desirable and unmet need.